Differential MR/GR Activation in Mice Results in Emotional States Beneficial or Impairing for Cognition

Corticosteroids regulate stress response and influence emotion, learning, and memory via two receptors in the brain, the high-affinity mineralocorticoid (MR) and low-affinity glucocorticoid receptor (GR). We test the hypothesis that MR- and GR-mediated effects interact in emotion and cognition when a novel situation is encountered that is relevant for a learning process. By adrenalectomy and additional constant corticosterone supplement we obtained four groups of male C57BL/6J mice with differential chronic MR and GR activations. Using a hole board task, we found that mice with continuous predominant MR and moderate GR activations were fast learners that displayed low anxiety and arousal together with high directed explorative behavior. Progressive corticosterone concentrations with predominant action via GR induced strong emotional arousal at the expense of cognitive performance. These findings underline the importance of a balanced MR/GR system for emotional and cognitive functioning that is critical for mental health

Post-Training Reward Partially Restores Chronic Stress Induced Effects in Mice

Reduced responsiveness to positive stimuli is a core symptom of depression, known as anhedonia. In the present study, we assessed the expression of anhedonia in our chronic stress mouse model using a subset of read-out parameters. In line with this, we investigated in how far chronic stress would affect the facilitating effect of post-training self-administration of sugar, as we previously observed in naïve mice. Male C57BL/6J mice were repeatedly and at unpredictable times exposed to rats (no physical contact) over the course of two weeks. Following novelty exploration, (non-) spatial learning and memory processes with and without post-training sugar acting as reinforcer, emotionality, reward sensitivity and corticosterone levels were determined. We found that (1) the effects of chronic stress persisted beyond the period of the actual rat exposure. (2) Post-training self-administration of sugar as reinforcer improved spatial performance in naïve mice, whereas (3) in stressed mice sugar partially “normalized” the impaired performance to the level of controls without sugar. Chronic stress (4) increased behavioral inhibition in response to novelty; (5) induced dynamic changes in the pattern of circadian corticosterone secretion during the first week after rat stress and (6) increased the intake of sucrose and water. (7) Chronic stress and sugar consumed during spatial training facilitated the memory for the location of the sucrose bottle weeks later. Concluding, our chronic stress paradigm induces the expression of anhedonia in mice, at different levels of behavior. The behavioral inhibition appears to be long lasting in stressed mice. Interestingly, sugar consumed in close context with spatial learning partially rescued the stress-induced emotional and cognitive impairments. This suggests that reward can ameliorate part of the negative consequences of chronic stress on memory

Stress-induced enhancement of mouse amygdalar synaptic plasticity depends on glucocorticoid and ß-adrenergic activity.

BACKGROUND: Glucocorticoid hormones, in interaction with noradrenaline, enable the consolidation of emotionally arousing and stressful experiences in rodents and humans. Such interaction is thought to occur at least partly in the basolateral nucleus of the amygdala (BLA) which is crucially involved in emotional memory formation. Extensive evidence points to long-term synaptic potentiation (LTP) as a mechanism contributing to memory formation. Here we determined in adolescent C57/Bl6 mice the effects of stress on LTP in the LA-BLA pathway and the specific roles of corticosteroid and β-adrenergic receptor activation in this process. PRINCIPAL FINDINGS: Exposure to 20 min of restraint stress (compared to control treatment) prior to slice preparation enhanced subsequent LTP induction in vitro, without affecting baseline fEPSP responses. The role of glucocorticoid receptors, mineralocorticoid receptors and β2-adrenoceptors in the effects of stress was studied by treating mice with the antagonists mifepristone, spironolactone or propranolol respectively (or the corresponding vehicles) prior to stress or control treatment. In undisturbed controls, mifepristone and propranolol administration in vivo did not influence LTP induced in vitro. By contrast, spironolactone caused a gradually attenuating form of LTP, both in unstressed and stressed mice. Mifepristone treatment prior to stress strongly reduced the ability to induce LTP in vitro. Propranolol normalized the stress-induced enhancement of LTP to control levels during the first 10 min after high frequency stimulation, after which synaptic responses further declined. CONCLUSIONS: Acute stress changes BLA electrical properties such that subsequent LTP induction is facilitated. Both β-adrenergic and glucocorticoid receptors are involved in the development of these changes. Mineralocorticoid receptors are important for the maintenance of LTP in the BLA, irrespective of stress-induced changes in the circuit. The prolonged changes in BLA network function after stress may contribute to effective memory formation of emotional and stressful events

Corticosterone concentrations determined in blood plasma, before, and 1 and 6 days after chronic stress.

<p>Using tail-incision, blood was withdrawn during the light period of the day at A) 09∶00 a.m., 13∶00 and 17∶00 p.m. to determine the corticosterone (ng/ml) levels; B) Overall corticosterone concentration during the light period, expressed as Area Under the Curve (AUC_total). Data represent mean ± SEM; *p<0.05 1-day post-stress vs. before stress and/or 6-days post-stress.</p

Chronic stress increases the behavioral inhibition of responses to novelty.

<p>Behavioral responses to the novel environment of the circular hole board (5 min free exploration trial - FET-1) were assessed one week after rat stress. A) Locomotor activity expressed as path length in meters; B) velocity on the board (cm/s); C) number of hole visits; D) number of rim dips; E) typical exploration pattern of a control and a stressed mouse. Data represent mean ± SEM; *p<0.05.</p

Behavioral parameters determined during the 5 min free exploration trials (FET-2 and FET-3).

<p>FET-2 was assessed three days after spatial training, and FET-3 one day after reversal training. Data represent mean ± SEM. Behavioral parameters that differ significantly are <b>bold</b>; p<0.05.</p>*<p>between groups control vs. stress;</p>#<p>within groups, <b>^∼</b>FET-2 vs. FET-3; n.a.  =  not applicable.</p

Stressed mice display reduced flexibility in directed search; sugar partially restores.

<p>Three days after the last spatial acquisition training trial, the percentage of time spent in the exit zone (15 cm radius) was determined during 5 min of free exploration trial 2 (FET-2). Data represent mean ± SEM; p<0.05 *control vs. stress; ^∼no-sugar vs. sugar.</p

Behavioral parameters expressed in the light area of the light-dark box during 5 min exposure.

<p>Data represent mean ± S.E.M. Behavioral parameters that differ significantly are <b>bold</b>; p<0.05.</p>*<p>between groups control vs. stress;</p>#<p>within groups.</p